Abstract by Eranga Roshan Balasooriya Loku Balasooriyage
Eranga Roshan Balasooriya Loku Balasooriyage
Chemistry and Biochemistry
14-3-3z mediated mechanisms of cancer cell survival in hypoxia
Hypoxia is a common stress within solid tumors that cancer cells must overcome in order to survive. However, the mechanisms by which cancer cells adapt and survive in hypoxia are not completely understood. We hypothesize a protein called 14-3-3z promotes cancer cell survival in hypoxia by coordinating pro-survival signaling pathways. We recently discovered a hypoxia-induced interaction between 14-3-3z and a Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1. By using chemical inhibitors and CRISPR knock-out approaches, my data suggest that AMPK phosphorylates TAK1 at S439, which allows 14-3-3z to bind and activate TAK1. Furthermore, CRISPR deletion of TAK1 from breast cancer cells makes them sensitive to hypoxia-mimicking treatments. Based on these data, I hypothesize that hypoxia activates AMPK, which in turn activates TAK1 through phosphorylation at S436 and 14-3-3z binding. This results in TAK1-mediated phosphorylation of IKK and NF-kB activation, resulting in upregulation of pro-survival genes. Together, these data suggest a novel mechanism of cancer cell survival in hypoxia.